Effects of protein-coding variants on blood metabolite measurements and clinical biomarkers in the UK Biobank.
Am J Hum Genet
; 110(3): 487-498, 2023 03 02.
Article
en En
| MEDLINE
| ID: mdl-36809768
ABSTRACT
Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10-8) for 205 distinct genes that involved 1,968 significant relationships for the Nightingale blood metabolite measurements and 331 for the clinical blood biomarkers. These include associations for rare non-synonymous variants in PLIN1 and CREB3L3 with lipid metabolite measurements and SYT7 with creatinine, among others, which may not only provide insights into novel biology but also deepen our understanding of established disease mechanisms. Of the study-wide significant clinical biomarker associations, 40% were not previously detected on analyzing coding variants in a GWAS in the same cohort, reinforcing the importance of studying rare variation to fully understand the genetic architecture of metabolic blood measurements.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Predisposición Genética a la Enfermedad
/
Estudio de Asociación del Genoma Completo
Tipo de estudio:
Prognostic_studies
Límite:
Humans
País/Región como asunto:
Europa
Idioma:
En
Revista:
Am J Hum Genet
Año:
2023
Tipo del documento:
Article
País de afiliación:
Reino Unido